The Long-Term Objective of this proposed rsearch is to provide new information to clarify and identify the fundamental metabolic and endocrinologic abnormalities which contribute to the glucose dyshomeostasis of sepsis and septic shock. Particular emphasis will be placed on the novel role of macrophage secretion products (monokines) and their effects on the pathophysiology of endocrine dysfunction of septic shock. The Specific Aims of this proposal include: a) a determination of the nature and extent of pancreatic islet dysfunction during sepsis and endotoxicosis. b) an evaluation of the inherent ability of the endocrine pancreas to secrete insulin and glucagon during sepsis and a comparison to the abnormal secretory state of the pancreas during endotoxicosis. c) an investigation of the ability of monokines (especially Interleukin) 1) to induce pancreatic islet dysfunction and a comparison of the latter to the islet dysfunction during endotoxicosis and sepsis. In addition, the general mechanisms by which monokines alter pancreatic islet function will be compared to those determined for islet dysfunction during endotoxicosis and sepsis. The Methodology which will be used to achieve the objectives of this proposal include the use of three rat models of sepsis: 1) The cecal ligation and puncture model of fulminating peritonitis, 2) The intravenous bolus injection of endotoxin (lipopolysaccharide derived from gram-negative bacteria), and 3) the slow, continuous intravenous infusion of endotoxin by minipump. Determination of pancreatic islet secretion of insulin and glucagon by radioimmunoassay will be achieved by: 1) perfusion of the rat pancreas preparation in vitro, and 2) incubation of rat pancreatic islets of Langerhans, isolated by collagenase digestion. Health Relatedness: The studies promise to provide fundamental knowledge concerning the mechanisms by which the host response to infection leads to abnormal endocrine function and thereby to abnormal control of metabolism. In addition, these studies may provide a new understanding regarding the role of monokines in the physiological regulation, as well as the pathophysiological regulation, of endocrine pancreatic function.